Gaucher disease is due to a deficiency of glucocerebrosidase, resulting in the accumulation of the glycolipid glucocerebroside. It is the most common glycolipid storage disease with nearly 9% of the Ashkenazi Jewish population is due primarily to one point mutation located at nt 1226 in the cDNA. A number of other point mutations and gene rearrangements have been documented, but the mutations in about 25% of Gaucher disease alleles remain unidentified. The detection of additional common mutations that cause Gaucher disease is of considerable practical importance because we believe that only if some 90 to 95% of mutations can readily be detected can screening for this disease be implemented. Based on linkage data we have proposed that at least one other fairly common mutation exists. Our studies thus far suggest that the unknown mutation is probably outside the coding region, and we plan to try to identify it by cloning and sequencing some of the unknown mutant genes. We will also develop more facile methods for detecting mutations in the coding regions, sequencing single stranded DNA amplified by PCR in such a way as to avoid amplifying the highly homologous, tightly linked pseudogene. We also plan to search for deletions of the glucocerebrosidase gene in patients who have been erroneously classified as homozygotes for one of the known mutations. We have obtained DNA from over 100 Gaucher disease patients and have had an opportunity to examine the majority of these. As we study more patients and identify additional mutations we will be able to refine the genotype/phenotype relationship in this disease group. We are performing clinical trials with the infusion of mannose-terminated glucocerebrosidase given at more frequent intervals at a lower dosage (and therefore lower cost) than has been done previously. We will study the kinetics of in vitro enzyme uptake into monocytes and cultured macrophages derived from patients with Gaucher disease in order to obtain information regarding receptor affinity, density and turnover, so as to be able to optimize in vivo treatment strategies.